Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
  • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
  • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
  • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
  • C07D477/20—Sulfur atoms
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
• one object of the present invention is to provide novel 3-pyrrolidinylthio-1-azabicyclo[ 3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms and are useful as antimicrobial agents.
• Another object of the present invention is to provide processes for the preparation of novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and salts thereof.
• a further object of the present invention is to provide a pharmaceutical composition
• a pharmaceutical composition comprising, as an active ingredient, said 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
• Still further object of the present invention is to provide a use of said 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof as a medicament and in the treatment of infectious diseases by pathogenic microorganisms in human being or animal.
• R 2 is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl
• R 3 is hydrogen or lower alkyl
• R 4 is unsaturated heterocyclic group which may be substituted by suitable substituent(s)
• R 5 is hydrogen, lower alkanimidoyl or imino-protective group
• A is lower alkylene
• Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g.
• a salt with an acid such as inorganic acid addition salt (e.g.
• hydrochloride hydrobromide, sulfate, phosphate, etc.
• an organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.
• a salt with a basic or acidic amino acid e.g. arginine, aspartic acid , glutamic acid, etc.
• an intermolecular or intramolecular quarternary salt e.g. arginine, aspartic acid , glutamic acid, etc.
• the said intermolecular quarternary salt can be formed in case that the unsaturated heterocyclic group in R 4 in the compound (I) contains tertiary nitrogen atom (e.g. imidazolyl, pyrazolyl, 4-imidazolin-1-yl, etc.), and suitable intermolecular quaternary salt may include 1- and/or 3-substituted-1-imidazolio (lower)alkylsulfate such as 1- and/or 3-(lower)alkyl-1-imidazolio (lower)alkylsulfate (e.g.
• the said intramolecular salt can be formed in case that the unsaturated heterocyclic group in R 4 in the compound (I) contains tertiary nitrogen atom (e.g. imidazolyl, pyrazolyl, 4-imidazolin-1-yl, etc.) and R 1 is carboxy, and suitable intramolecular salt may include 1-and/or 3-substituted-1-imidazolio carboxylate such as 1-and/or 3-(lower)alkyl-1-imidazolio carboxylate (e.g.
• 3-acetonyl-1-imidazolio carboxylate 3-propionylmethyl-1-imidazolio carboxylate, 3-butyrylmethyl-1-imidazolio carboxylate, 3-acetylethyl-1-imidazolio carboxylate, 3-acetylpropyl-1-imidazolio carboxylate, 3-acetylbutyl-1-imidazolio carboxylate, etc.), 3-phenyl(or nitrophenyl)(lower)alkoxycarbonyl(lower)alkyl-1-imidazolio carboxylate [e.g.,
• the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes. ##STR2## in which R 1 , R 2 , R 3 , R 4 , R 5 and A are each as defined above,
• R a 1 is protected carboxy
• R a 2 is protected hydroxyl(lower)alkyl
• R b 2 is hydroxy(lower)alkyl
• R a 4 is unsaturated heterocylic group containing tertiary nitrogen atom, which may be substituted by suitable substituent(s),
• R a .spsp.+ 4 is unsaturated heterocyclic group containing quaternary nitrogen atom, which may be substituted by suitable substituent(s),
• R a 5 is imino-protective group, is lower alkanimidoyl
• R b 5 is lower alkanimidoyl
• R 6 is lower alkyl optionally substituted by a group consisting of carboxy and acyl
• X is an acid residue
• Suitable “protected carboxy” may include esterified carboxy wherein “esterified carboxy” can be referred to the ones as mentioned below.
• ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g.
• acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)-propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)p
• 2-mesylethyl ester, etc. mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester [e.g.
• benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis[methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g.
• phenyl ester 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
• More preferable example of the protected carboxy thus defined may be C 2 -C 4 alkenyloxycarbonyl and phenyl( or nitrophenyl)(C 1 -C 4 )alkoxycarbonyl, and the most preferable one may be 4-nitrobenzyloxycarbonyl.
• Suitable "hydroxy(lower)alkyl” may include straight or branched lower alkyl having hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1-(hydroxymethyl)ethyl, 1-hydroxy-1-methylethyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like, in which more preferable example may be hydroxy(C 1 -C 4 )alkyl and the most preferable one may be 1-hydroxyethyl.
• Suitable "protected hydroxy(lower)alkyl” means aforementioned hydroxy(lower)alkyl, in which the hydroxy group is protected by a conventional hydroxy-protective group such as those mentioned in the explanation of imino-protective group as mentioned below; ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), etc.; trisubstituted silyl such as tri[lower)alkylsilyl (e.g.
• trimethylsilyl triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl, etc.
• triarylsilyl e.g. triphenylsilyl, etc.
• triar(lower)alkylsilyl e.g. tribenzylsilyl, etc.
• protected hydroxy(lower)alkyl thus defined may be [phenyl(or nitrophenyl)(C )alkoxy]carbonyloxy( )alkyl and [tri(C 1 -C 4 )alkylsilyl]oxy(C 1 -C 4 )alkyl.
• Suitable "lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferable example may be C 2 -C 4 alkyl and the most preferable one may be methyl.
• Suitable unsaturated heterocyclic group moiety of "unsaturated heterocyclic group which may be substituted by suitable substituent(s)" may include unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as oxygen, sulfur or nitrogen atom.
• Preferable unsaturated heterocyclic group may be unsaturated 3 to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl- (e.g. 2-imidazolinyl, etc.), pyrazolyl, pyrazolinyl, pyridyl, pyridyl N-oxide, pyridinio, dihydropyridy-l, tetrahydropyridy-l [e.g.
• 1,2,3,6-tetrahydropyridyl, etc.] pyrimidinyl, pyrimidinio, pyrazinyl, pyrazinio, pyridazinyl, pyridazinio, triazinyl [e.g. 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl], tetrahydrotriazinyl e.g. 1,2,5,6-tetrahydro-1,2,4-triazinyl, 1,4,5,6-tetrahydro-1,2,4-triazinyl, etc.], triazinio, triazolyl [e.g.
• heterocyclic group may be substituted by one or more, preferably one to three suitable substituent(s) such as oxo; carboxy(lower)alkyl, which is the aforementioned lower alkyl group substituted by carboxy; protected carboxy(lower)alkyl, which is the carboxy(lower)alkyl as mentioned above, in which the carboxy group is protected by a suitable carboxy-protective group to form so-called "esterified carboxy" as mentioned above; amino; protected amino in which the amino-protective group may be the same as those for the imino-protective group as mentioned below; lower alkylamino (e.g.
• ureido(lower)alkyl e.g. ureidomethyl, ureidoethyl, ureidopropyl, ureidohexyl, etc.
• carbamoyl e.g. carbamoylmethyl, etc.
• lower alkyl as mentioned above; lower alkanoyl(lower)alkyl (e.g. acetylmethyl, etc.); amino(lower)alkyl (e.g.
• imidazolyl e.g. imidazol-1-yl, etc.
• pyrazolyl e.g. pyrazol-1-yl, etc.
• imidazolinyl e.g. 4-imidazolin-1-yl-, etc.
• oxoimidazolinyl e.g. 2-oxo-4-imidazolin-1-yl, etc.
• Suitable "unsaturated heterocyclic group containing tertiary nitrogen atom, which may be substituted by suitable substituent(s)" may include unsaturated, monocyclic or polycyclic heterocyclic group containing tertiary nitrogen atom and/or other hetero-atom(s) such as oxygen, sulfur and nitrogen atom.
• pyrrolyl e.g. pyrrol-1-yl, etc.
• pyrrolinyl e.g. 2-pyrrolin-1-yl, etc.
• imidazolyl imidazolinyl (e.g. 2-imidazolinyl 4-imidazolin-1-yl, etc)
• pyrazolyl pyrazolinyl (e.g. pyrazolin-1-yl, etc.)
• pyridyl dihydropyridyl (e.g.
• 1,4-dihydropyridin-1-yl, etc. 1,4-dihydropyridin-1-yl, etc.
• tetrahydropyridyl e.g. 1,2,3,6-tetrahydropyridin-1-yl, etc.
• pyrimidinyl pyrazinyl, pyridazinyl, triazinyl [e.g. 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl]
• tetrahydrotriazinyl e.g. 1,2,5,6-tetrahydro-1,2,4-triazin-1-yl, 1,4,5,6-tetrahydro-1,2,4-triazin-1-yl, etc.
• triazolyl e.g.
• heterocyclic group may be substituted by one or more, preferably one to three suitable substituent(s) such as those given for the explanation of "unsaturated heterocyclic group which may be substituted by suitable substituent(s)".
• heterocyclic group is imidazolyl, pyrazolyl or imidazolinyl
• the imino-moiety(ies) thereof may be protected by conventional imino-protective group(s) as mentioned below.
• unsaturated heterocyclic group containing tertiary nitrogen atom which may be substituted by suitable substituent(s) may be:
• imidazolyl e.g. imidazol-1-yl, etc.
• pyrazolyl e.g. pyrazol-1-yl, etc
• imidazolin-1-yl e.g. 4-imidazolin-1-yl, etc.
• 2-oxoimidazolin-1-yl e.g. 2-oxo-4-imidazolin-1-yl, etc.
• Suitable "unsaturated heterocyclic group containing quaternary nitrogen atom, which may be substituted by suitable substituent(s)" may be the same as those for "unsaturated heterocyclic group containing tertiary nitrogen atom", in which the tertiary nitrogen atom is substituted by "lower alkyl optionally substituted by a group consisting of carboxy and acyl" for "R 6 " as mentioned below to form tertiary nitrogen atom. And further in case that said heterocyclic group is imidazolyl, pyrazolyl or imidazolinyl, the imino-moiety(ies) thereof may be protected by conventional imino-protective group(s) as mentioned below.
• unsaturated heterocyclic group containing quaternary nitrogen atom which may be substituted by suitable substituent(s) may be:
• Suitable "imino-protective group” may include acyl such as carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
• the aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g.
• alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
• alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.)
• alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.)
• cycloalkanecarbonyl such as cyclo(
• the aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
• aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
• acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl(e.g. nitrobenzyloxycarbonyl, etc.), and the like.
• amino-protective group thus defined may be C 2 -C 4 alkenyloxycarbonyl and phenyl(or nitrophenyl)(C 1 -C 4 )alkoxycarbonyl and the most preferable one may be 4-nitrobenzyloxycarbonyl.
• Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C 1 -C 4 alkylene and the most preferable one may be methylene.
• Suitable “acid residue” may include an inorganic acid residue such as azido, halogen (e.g. chlorine, bromine, fluorine or iodine), and the like, an organic acid residue such as acyloxy (e.g. benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, etc.), and the like, in which more preferable example may be halogen and the most preferable one may be iodine.
• halogen e.g. chlorine, bromine, fluorine or iodine
• organic acid residue such as acyloxy (e.g. benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, etc.), and the like, in which more preferable example may be halogen and the most preferable one may be iodine.
• Suitable "lower alkyl substituted by a group consisting of carboxy and acyl” may include aforementioned lower alkyl group, which is substituted by one or more, preferably one to three suitable substituent(s) such as carboxy, acyl as mentioned above, and the like, in which more preferable example may be carboxy(C 1 -C 4 )alkyl, phenyl(or nitrophenyl)(C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkanoyl(C 1 -C 4 )alkyl and carbamoyl(C 1 -C 4 )alkyl and the most preferable one may be carboxymethyl, 4-nitrobenzyloxycarbonylmethyl, acetonyl and carbamoylmethyl.
• Suitable "lower alkanimidoyl” may be straight or branched one such as formimidoyl, acetimidoyl, propionimidoyl, butyrimidoyl, isovalerimidoyl, pentanimidoyl, hexanimidoyl, and the like, in which more preferable one may be (C 1 -C 4 )alkanimidoyl and the most preferable one may be formimidoyl.
• the compound (I) or salts thereof can be prepared by reacting the compound (II) or a reactive derivative at the oxo group thereof or salts thereof with the compound (III) or salts thereof.
• Suitable salts of the compound (II) may be salts with bases such as those given for the compound (I).
• the reactive derivative at the oxo group of the compound (II) can be represented by the following formula (II'), which is preferably used in this reaction and can be prepared by reacting the compound (II) or salts thereof with an acylating agent. ##STR4## in which R 1 , R 2 and R 3 are each as defined above, and
• R 7 is acyl as exemplified for the imino-protective group and further O,O-substituted phosphono derived from, for example, organic phosphoric acid mentioned hereinbelow.
• Suitable acylating agents may include conventional ones which can introduce the acyl group as mentioned above into the compound (II), and preferable acylating agents may be organic sulfonic or phosphoric acid or its reactive derivative such as acid halide, acid anhydride, and the like, for example, arenesulfonyl halide (e.g. benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc.), arenesulfonic anhydride (e.g.
• benzenesulfonic anhydride p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, etc.
• lower alkanesulfonyl halide which may have additional halogen (e.g. methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.), lower alkanesulfonic anhydride which may have halogen (e.g.
• methanesulfonic anhydride ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.
• di(lower)alkyl phosphorohaloridate e.g. diethyl phosphorochloridate, etc.
• diaryl phosphorohaloridate e.g. diphenyl phosphorochloridate, etc.
• This acylation reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.
• a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.
• the reaction is preferably carried out in the presence of a conventional condensing agent such as carbodiimide compound [e.g. N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.]; N,N'-carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole); keteneimine compound (e.g.
• This acylation reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, N,N-diisopropyl-N-ethylamine, etc.), pyridine compound [e.g.
• an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
• alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
• alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
• tri(lower)alkylamine e.g. trimethylamine, triethylamine, N,N
• N,N-di(lower)alkylaminopyridine such as N,N-dimethylaminopyridine, etc.
• quinoline N-lower alkylmorpholine (e.g. N-methylmorpholine, etc.)
• N,N-di(lower)alkylbenzylamine e.g. N,N-dimethylbenzylamine, etc.
• alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium butoxide, etc.
• reaction temperature of this acylation reaction is not critical and the reaction is usually carried out under from cooling to warming.
• the compound (II') or salts thereof can be used with or without isolation for the subsequent reaction with the compound (III) or salts thereof.
• Suitable salts of the compound (III) may be the same as those for the compound (I) and silver salt.
• reaction of the compound (II) or its reactive derivative or salts thereof with the compound (III) or salts thereof can be carried out in the presence of an organic or inorganic base such as those given in the explanation of the acylation reaction as stated above.
• This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as those given in the explanation of the acylation reaction.
• the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
• the compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to removal reaction of the carboxy-protective group on R a 1 .
• Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I).
• the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
• Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g.
• an alkalimetal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
• an alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
• alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
• alkaline earth metal hydride e.g. calcium hydride,
• sodium carbonate, potassium carbonate, etc. sodium carbonate, potassium carbonate, etc.
• alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
• an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
• Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).
• organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
• an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
• the acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc.).
• the hydrolysis can be carried out in the presence of tri(lower)alkylammonium halide (e.g. tributylammonium fluoride, etc.).
• tri(lower)alkylammonium halide e.g. tributylammonium fluoride, etc.
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
• a liquid base or acid can be also used as the solvent.
• the reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
• the reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g.
• nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
• platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
• the reaction is preferably carried out around neutral condition.
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
• a conventional solvent which does not adversely influence the reaction
• alcohol e.g. methanol, ethanol, propanol, etc.
• dioxane etrahydrofuran
• acetic acid e.g. phosphate buffer, acetate buffer, etc.
• buffer solution e.g. phosphate buffer, acetate buffer, etc.
• the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
• the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.
• Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), di[1,2-bis(diphenyl phosphino)ethane]palladium(0), tetrakis(triphenyl phosphite)palladium(0), tetrakis(triethyl phosphite)palladium(0), and the like.
• a palladium-ligand complex such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), di[1,2-bis(diphenyl phosphino)ethane]palladium(0), tetrakis(triphenyl phosphite)palla
• the reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholine, N-methylaniline, etc.), an activated methylene compound (e.g. dimedone, benzoylacetate, 2-methyl-3-oxoyaleric acid, etc.), a cyanohydrin compound (e.g. ⁇ -tetrahydropyranyloxybenzyl cyanide, etc.), lower alkanoic acid or a salt thereof e.g. formic acid, acetic acid, ammonium formate, sodium acetate, etc.), N-hydroxysuccinimide, and the like.
• amine e.g. morpholine, N-methylaniline, etc.
• an activated methylene compound e.g. dimedone, benzoylacetate, 2-methyl-3-oxoyaleric acid, etc.
• a cyanohydrin compound e.g. ⁇
• This reaction can be carried out in the presence of a base such as lower alkylamine (e.g. butylamine, triethyamine, etc.), pyridine, and the like.
• a base such as lower alkylamine (e.g. butylamine, triethyamine, etc.), pyridine, and the like.
• the reaction can preferably be carried out in the presence of the corresponding ligand (e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.).
• the corresponding ligand e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc., or a mixture thereof.
• a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc., or a mixture thereof.
• the removal reaction can be selected according to the kind of carboxy-protective group to be removed.
• the present process includes within the scope thereof a case that the hydroxy- and/or carboxy- and/or amino-protective group(s) on R 2 and/or R 4 , and/or imino-protective group of R 5 , and/or additional carboxy-protective group are removed at the same time during the reaction.
• the compound (I-d) or salts thereof can be prepared by subjecting the compound (I-c) or salts thereof to removal reaction of the imino-protective group on R a 5 .
• Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
• This reaction is usually carried out by a conventional method such as hydrolysis, reduction and the like.
• the present process includes within the scope thereof a case that the carboxy- and/or hydroxy- and/or amino-protective group(s) on R 1 and/or R 2 and/or R 4 , and/or additional carboxy-protective group are removed at the same time during the reaction.
• the compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to removal reaction of the hydroxy-protective group on R a 2 .
• Suitable salts of the compounds (I-e) and (I-f) - may be the same as those for the compound (I).
• This reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
• reaction conditions e.g. reaction temperature, solvent, etc.
• the removal of this protective group can also be carried out in the presence of tetra(lower)alkylammonium fluoride (e.g. tetrabutylammonium fluoride, etc.).
• tetra(lower)alkylammonium fluoride e.g. tetrabutylammonium fluoride, etc.
• the present process includes within the scope thereof a case that the carboxy- and/or hydroxy- and/or amino-protective group(s) on R 1 and/or R 4 , and/or the imino-protective group of R 5 , and/or additional carboxy-protective group are removed at the same time during the reaction
• the compound (I-h) or salts thereof can be prepared by reacting the compound (I-g) or salts thereof with the compound (IV) .
• Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I).
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dioxane, tetrahydrofuran, acetone, acetonitrile, etc., or a mixture thereof
• the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
• the compound (I-i) or salts thereof can be prepared by reacting the compound (I-d) or salts thereof with lower alkanimidoylating agent.
• Suitable salts of the compound (I-i) may be the same as those for the compound (I).
• Suitable lower alkanimidoylating agent may be conventional ones which can introduce the lower alkanimidoyl group as mentioned above into the compound (I-d), and said preferable agent may be lower alkyl(lower)alkanimidate (e.g. methyl formimidate, ethyl formimidate, methyl acetimidate, ethyl acetimidate, ethyl propionimidate, ethyl butyrimidate, ethyl isovalerimidate, ethyl pentanimidate, ethyl hexanimidate, etc.), are lower)alkyl lower alkanimidate (e.g.
• (lower)alkanimidoyl halide e.g. formimidoyl chloride, formimidoyl bromide, acetimidoyl chloride, acetimidoyl, bromide, propionimidoyl chloride, butyrimidoyl chloride, isovalerimido-yl chloride, pentanimidoyl chloride, hexanimidoyl chloride, etc.
• an acid addition salt thereof e.g. formimidoyl chloride, formimidoyl bromide, acetimidoyl chloride, acetimidoyl, bromide, propionimidoyl chloride, butyrimidoyl chloride, isovalerimido-yl chloride, pentanimidoyl chloride, hexanimidoyl chloride, etc.
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dioxane, water, methanol, ethanol, buffer solution (e.g. phosphate buffer, etc.), etc., or a mixture thereof.
• a conventional solvent which does not adversely influence the reaction
• tetrahydrofuran, dioxane water, methanol, ethanol, buffer solution (e.g. phosphate buffer, etc.), etc., or a mixture thereof.
• the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
• the compound (III-a) or salts thereof can be prepared by reacting the compound (IV) or a reactive derivative at the hydroxy group thereof or salts thereof with the compound (V) or salts thereof
• Suitable salts of the compounds (III-a), (IV) may be the same as those for the compound (I).
• Suitable salts of the compound (V) may be salts with bases such as those given for the compound (I).
• Suitable reactive derivative at the hydroxy group of the compound (IV) may include a conventional one such as halide (e.g. chloride, bromide, iodide, etc.), sulfonate (e.g. methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), and the like, in which more preferable example may be sulfonate
• halide e.g. chloride, bromide, iodide, etc.
• sulfonate e.g. methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
• more preferable example may be sulfonate
• the starting compound (IV) of this method is new and can be prepared by the methods described in the Preparations mentioned below.
• the compound (V) may be ar(lower)alkanethiol such as mono- or di- or triphenyl(lower)alkanethiol (e.g. phenylmethanethiol, diphenylmethanethiol, triphenylmethanethiol, etc.), thio(lower)alkanoic S-acid (e.g. thioacetic S-acid, etc.) or salts thereof, thioarenoic S-acid or salts thereof (e.g.
• thiobenzoic S-acid etc.
• more preferable example may be triphenyl(C 1 -C 4 )alkanethiol, thio(C 1 -C 4 )alkanoic S-acid or alkali metal salts thereof and thio(C 6 -C 10 )arenoic S-acid
• 6TM10 or alkali metal salts thereof and the most preferable one may be triphenylmethanethiol, thioacetic S-acid and potassium thioacetate.
• the starting compound (IV) of the present reaction is preferably used in the form of its reactive derivative at the hydroxy group, and in such a case, this reaction is usually carried out in the presence of an organic or inorganic base such as those exemplified in the explanation of Process 2.
• suitable example of compound (V) may be thio(lower)alkanoic S-acid or thioarenoic S-acid
• this exaction is preferably carried out in the presence of a conventional condensing agent such as combination of triarylphosphine (e.g. triphenylphosphine, etc.) and di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, etc.).
• a conventional condensing agent such as combination of triarylphosphine (e.g. triphenylphosphine, etc.) and di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, etc.).
• This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, methanol, ethanol, propanol, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
• a conventional solvent which does not adversely influence the reaction such as dichloromethane, methanol, ethanol, propanol, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
• the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
• the compound (III) or salts thereof can be prepared by subjecting the compound (III-a) or salts thereof to elimination reaction of the mercapto-protective group.
• This elimination reaction can be carried out by a conventional method as described below, which can be selected according to the kind of mercapto-protective group to be eliminated.
• the protective groups may be ar(lower)alkyl group
• it can generally be eliminated by treating, for example, with a silver compound (e.g. silver nitrate, silver carbonate, etc.).
• a silver compound e.g. silver nitrate, silver carbonate, etc.
• reaction with the silver compound as stated above is preferably carried out in the presence of an organic base (e.g. pyridine, etc.).
• an organic base e.g. pyridine, etc.
• the resultant silver salt of compound (III) can be transformed into its alkali metal salt, if necessary, by reacting with alkali metal halide (e.g. sodium iodide, potassium iodide, etc.).
• alkali metal halide e.g. sodium iodide, potassium iodide, etc.
• the protective groups may be acyl group
• it can generally be eliminated by solvolysis such as hydrolysis using an acid or base, alcoholysis using a base, and the like.
• Suitable acid or base used in these reactions may be the same such as those given in the explanation of hydrolysis of the Process 2.
• the hydrolysis is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, etc.), pyridine, N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the base or acid to be used is in liquid, it can also be used as a solvent.
• the alcoholysis is usually carried out in a conventional alcohol such as methanol, ethanol, and the like.
• the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
• the object compounds (I), (I-b), (I-d), (I-f), (I-h) and (I-i) obtained according to the Processes 1 to 6, can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
• the object compound (I) and pharmaceutically acceptable salts thereof of the present invention are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents
• the object compound (I) possessing more potent antimicrobial activity can be represented by the following formula: ##STR6## in which R b 2 , R 3 , R 4 and A are each as defined above, and pharmaceutically acceptable salts thereof.
• the compound (I) possessing the most potent antimicrobial activity can be represented by the following formula: ##STR7## in which R 3 , R 4 and A are each as defined above, and pharmaceutically acceptable salts thereof.
• test data on antimicrobial activity of the representative compound of the compound (I) of this invention is shown in the following.
• the object compound (I) and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
• pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
• the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like.
• auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
• the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between 1 mg and about 4,000 mg or even more per day may be administered to a patient.
• An average single dose of about 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg, of the object compound (I) of the present invention may be used in treating diseases infected by pathogenic microorganisms.
• Methanesulfonyl chloride (0.40 ml) was added to a suspension of (2S,4R)-4-hydroxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbon-yl)pyrrolidine (0.79 g) in a mixture of triethylamine (0.80 ml), tetrahydrofuran (16 ml) and dichloromethane (24 ml) at 0°-5° C., and the mixture was stirred at 0°-5° C. for one hour. The reaction mixture was poured into a mixture of water (50 ml) and dichloromethane (20 ml).
• Diphenyl chlorophosphate (0.16 ml) was added thereto at -10°-5° C. in a nitrogen stream, followed by stirring at -10°-5° C. for 30 minutes.
• a solution of (2S,4S)-2-(imidazol-1-yl)methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.26 g) in acetonitrile (2 ml) at -30°-25° C. and the mixture was stirred at 0°-10° C. for 2 hours.
• the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran.
• the residual solution was washed with ethyl acetate (20 ml ⁇ 2) and the organic solvent was removed by evaporation.
• the residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (10 ml), washed with a mixture of acetone and water (2:98 V/V), and eluted with a mixture of acetone and water (5:95 V/V).
• the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran.
• the residual solution was washed with ethyl acetate (50 ml ⁇ 2) and the organic solvent was removed by evaporation.
• the aqueous solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (50 ml), washed with water, eluted with a mixture of acetone and water (1:99 V/V).
• the fractions containing the desired compound were collected and evaporated in vacuo.
• the resulting residue 14.93 g was dissolved in a mixture of acetone (100 ml) and water (70 ml).
• the solution was passed through ion exchange resin, "Amberlist A-26" (Cl - type, Trademark, made by Rohm and Haas CO., Ltd.) (300 ml) and eluted with a mixture of acetone (600 ml) and water (420 ml).
• the eluates were collected and evaporated in vacuo to remove the organic solvent.
• the mixture was stirred at the same temperature for 1 hour.
• the reaction mixture was adjusted to pH 6 with conc. hydrochloric acid and the mixture was evaporated in vacuo to remove the organic solvent.
• the resulting aqueous solution (10 ml) was washed with ethyl acetate (10 ml) and chromatographed on nonionic adsorption resin, "Diaion HP-20" (20 ml) eluting in turn with water (40 ml) and 3% aqueous acetone (80 ml).
• the fractions containing the desired compound ware collected and evaporated in vacuo.
• the resulting residue (10 ml) was adjusted to pH 3.5 with 1N hydrochloric acid and the solution was passed through ion exchange resin, "Amberlist A-26" (10 ml) and eluted with water (30 ml). The eluate was evaporated in vacuo to give a residue. The residue was dissolved in ethanol (50 ml) and the solution was stirred under ice-cooling for 1 hour.

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